Stroke is a major cause of neurological disability and death, but most patients improve over weeks to months after stroke, suggesting that endogenous mechanisms exist for limiting and reversing the effects of brain ischemia. These include neuroprotection, which prevents the progression of reversible to irreversible injury, and neuroregeneration, which replaces lost cells, circuits and functions. In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from hypoxia in vitro and ischemia in vivo, promotes adult neurogenesis, improves histological and functional outcome after experimental stroke, and stimulates neurite outgrowth. These effects are mediated largely through the VEGFR2 receptor, although we have also found that VEGFB, which acts via VEGFR1, has some of the same actions. Other endogenous VEGF family members-VEGFC, VEGFD, and placental growth factor (PlGF)- have different receptor specificities, and little is known about their effects on the nervous system. We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members operate via distinct but overlapping signaling pathways to regulate diverse aspects of ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. This hypothesis will be tested by addressing the following specific aims: (1) Compare the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC; (2) Evaluate the ability of VEGFB and VEGFC to enhance repair and recovery in the post-acute phase following experimental stroke; (3) Identify the signal transduction pathways employed in the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC; and (4) Determine the contribution of endothelial cells to the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC. PUBLIC HEALTH RELEVANCE: In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from oxygen deprivation and brain ischemia, promotes the production of new neurons (neurogenesis), improves outcome after experimental stroke, and stimulates outgrowth of nerve processes (neurites). We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members (VEGFB and VEGFC) operate via distinct but overlapping signaling pathways to regulate ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. The proposed studies will help to delineate the potential and limitations of VEGF family members in the treatment of stroke.